Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord [Wijesekera L C, et al. Orphanet J Rare Dis. 2009 Feb. 3; 4:3].
Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, in which onset of symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. Limb symptoms can develop almost simultaneously with bulbar symptoms and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases.
Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% involve a mutation of the SOD1 gene (21q22.11), about 2-5% involve mutations of the TARDBP gene (1p36.22) encoding the TAR DNA-binding protein 43 (TDP-43) and 1-2% involve mutations of the VCP gene (9p13.3) coding for the Valosin Containing Protein. Two percent of apparently sporadic cases involve SOD1 mutations, and TARDBP mutations have also been identified in sporadic cases.
The cause of ALS is unknown although some genetic risk factors have been identified. Recent reviews on the role of environmental risk factors in the causation of ALS have concluded that there is no consistent association between a single environmental factor and risk of developing ALS. Most authors favor a hypothesis of complex genetic-environmental interaction as the causal factor for motor neuron degeneration.
The exact molecular pathway causing motor neuron degeneration in ALS is unknown, but as with other neurodegenerative diseases it is likely to involve a complex interplay between multiple pathogenic cellular mechanisms, which may not be mutually exclusive. These include: genetic factors, excitotoxicity, oxidative stress, mitochondrial dysfunction, impaired axonal transport, neurofilament aggregation, protein aggregation, inflammatory dysfunction and contribution of non-neuronal cells.
There is growing evidence that inflammatory dysfunction and non-neuronal cells may play a part in pathogenesis of ALS [Wijesekera L C, et al. Orphanet J Rare Dis. 2009 Feb. 3; 4:3]. Microglial and dendritic cell activation is a prominent pathology in human ALS and transgenic SOD1 mice. These activated non-neuronal cells produce inflammatory cytokines such as interleukins, COX-2, TNFα and MCP-1, and evidence of upregulation is found in cerebrospinal fluid or spinal cord specimens of ALS patients or in vitro models. Neuroinflammation via glial activation is now established as an important aspect of pathology in ALS [Philips T, et al. Lancet Neurol. 2011; 10: 253-263]. There is a marked activation or proliferation of both microglia and astrocytes at specific disease stages in humans in vivo [Turner M R, et al. Neurobiol Dis 2004; 15:601-9]. There is also evidence indicating impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers in both patients and animal models of ALS [Garbuzova-Davis S. Amyotroph Lateral Scler. 2008 December; 9(6):375-6].
Another non-neuronal cell of emerging significance is the mast cell. Mast cells are well known to play a prominent role in all inflammatory processes through expressing receptors for molecules that are usually involved in such reactions. Furthermore, mast cells release large amounts of various mediators that sustain the inflammatory network and modulate blood-brain barrier (BBB) permeability [Skaper S D, et al. Immunol 2014; 141:314-327]. Importantly, mast cells and neuronal cells are linked through the activation of microglia in response to pro-inflammatory cytokines released from mast cells [Skaper S D, et al. Immunol 2014; 141:314-327].
It has been observed in clinical practice that ALS patients experience different rates of disease progression. It is hypothesized that different rates of disease progression reflect differing pathogenesis of ALS, with ramifications as to the efficacy of therapies directed towards any specific mechanism of disease. That is to say, heterogeneity within the overall ALS population in terms of disease progression can be explained by distinct subpopulations of ALS patients.
There exist at least two highly distinct subpopulations of ALS patient within the overall ALS population, which can be distinguished from one another in terms of ‘fast progressor’ patients (referred to also as ‘aggressive ALS’) who progress at a relatively fast rate as measured via progression of a suitable clinical marker of disease burden, and ‘normal progressor’ patients (referred to also as ‘non-aggressive or moderately aggressive ALS’) who progress at a relatively slower rate. The former subgroup represents a more aggressive and heterogeneous form of disease with patients at higher risk of death (significantly shorter median survival time) or tracheostomy [Kimura F, et al. Neurology 2006; 66:265-267]. The latter “normal progressor” subgroup represents the majority of ALS patients.
There is no available treatment to stop or reverse the progressive course of ALS, whether is it non-aggressive or moderately aggressive ALS or aggressive ALS. There has been no advance in efficacy of available therapeutic agents over the last 20 years since registration of riluzole, the only authorized medicinal product for ALS. This is despite the fact that riluzole (100 mg) offers only modest survival benefits, very modest functional improvement and is an expensive drug, estimated to cost approximately $10,000 per year per patient in the US.
A comprehensive review by Miller and colleagues on the use of riluzole for ALS considered evidence from four randomized clinical trials involving 1477 ALS patients treated with riluzole [Miller R G, et al. Cochrane Database Syst Rev. 2012 Mar. 14; 3:CD001447]. Results from this meta-analysis indicated that riluzole 100 mg probably prolongs median survival in people with ALS by 2 to 3 months with respect to participants taking placebo and the safety of the drug is not a major concern. There are no data that directly measured quality of life from the published trials. Additionally, there was no beneficial effect of riluzole on patient function in any of the randomized trials considered separately. Only when data were combined was small beneficial effect on bulbar and limb function observed, but not on muscle strength; the authors however, warn that these functional results should be interpreted with caution.
Many symptomatic treatments, which do not slow disease progression but affect quality of life, appear helpful to individuals in the clinical setting (Table 1 lists the various symptomatic treatments commonly used for management of ALS [Jenkins T M, et al. Curr Opin Neurol. 2014 October; 27(5):524-31]). However, evidence of significant benefit is weak and further randomized clinical trials are required to provide a more robust evidence base. This opinion is reflected in a Cochrane systematic review of treatments for spasticity in ALS by Ashworth and colleagues (published in 2006 with update in 2011) [Ashworth N L, et al. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004156].
TABLE 1Summary of symptomatic treatments commonly usedin patients with ALS [adapted from Jenkins 2014]DrugPopulation indicated/Common usageBaclofenIndicated for the relief of spasticity of voluntary(Lioresal)muscle resulting from such disorders, for example,multiple sclerosis. In patients 0 to <18 years it isindicated for the symptomatic treatment of spasticityof cerebral origin, including ALS.HyoscineHypersalivationCarbocisteineDifficulty expectorating secretionsAmitriptylineNeuropathic painGabapentinNeuropathic painCitalopramDepression and emotional labilityVenlafaxineDepressionNortriptylineDepression
In conclusion, the treatment of ALS remains a challenge to clinicians because of the diversity and complexity of the disease itself and the lack of standard and clinically meaningful effective therapy.
Furthermore, existing treatments do not take into account the progression rate of the disease, i.e. non-aggressive or moderately aggressive ALS versus aggressive ALS.
None of the known approved or investigational drugs appear to represent a cure for ALS. Moreover, the efficacy of known drugs is limited and may decrease over time, with undesirable side effects reported. Thus, there exists a continuing need to identify new targeted drugs that possess greater efficacy to treat ALS, and in particular the non-aggressive or moderately aggressive ALS affecting the majority of ALS patients.